1. Technical Field
The present invention relates to a novel pyrimidinone compounds and the pharmaceutically acceptable salts thereof This invention also relates to a process for preparing the novel pyrimidinone compounds and a pharmaceutical composition containing the pyrimidinone compounds.
2. Background Art
Pyrimidinone derivatives according to this invention and the pharmaceutically acceptable salts thereof are useful as antagonists against angiotensin II, especially, in treatment of cardiovascular diseases caused by binding angiotensin II to its receptor.
Renin-angiotensin system plays a central role in the regulation of blood pressure in human body. Angiotensin II, consisting of eight amino acids, is produced through the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the arterial blood vessels of lung. Angiotensin II interacts with specific receptors present in blood vessels, smooth muscle, kidney, and adrenal gland, to induce the blood pressure and the electrolyte concentration to increase.
Thus, several antagonistic compounds have been developed to inhibit the effect of angiotensin II by selectively blocking its receptors.
Conventionally, peptide antagonists analogous to angiotensin II have been proposed, but their clinical applications have been limited because of their short half-life, oral inertia as well as local increase of blood pressure.
Recently, lots of researches have been reported in connection with non-peptide angiotensin II antagonists (U.S. Pat. No. 4,207,324, 4,340,598, 4,576,958, 4,582,847, and 4,880,804; European Patent Laying-Open Publication Nos. 028,834, 245,637, 253,310, 291,969, 323,841 and 324,377). European Patent Laying-Open Publication Nos. 028,834 and 253,310 disclose Imidazole derivatives substituted by biphenyl (for example, Losartan) and European Patent Laying-Open Publication No. 245,637, imidazopyridine derivatives (for example, L158,809) as potent angiotensin II antagonists.
In European Patent Laying-Open Publication Nos. 407,342, 419,048 and 445,811, pyrimidinone compounds similar to the compounds of this invention in their 6 membered heterocyclic ring structure are disclosed, including nitrogen which is very different from the 5 membered imidazole derivatives. But, the pyrimidinone compounds have lower activities than the imidazole derivatives described in the above mentioned application.
In the meantime, the inventors of this invention have filed a PCT application (WO 96-08476) for a novel compounds having noticeably high activities (in vitro (rabbit aorta), 60.about.70% inhibition for 10.sup.-8 to 10.sup.-9 mole in vitro blood vessel dilation study) which is 50 times higher than or equal to imidazole derivatives known in the above mentioned application.